2015 Receptor Recognition Mechanisms of Coronaviruses_ a Decade of Structural Studies

11 Pages·2015·2.13 MB·English

Receptor Recognition Mechanisms of Coronaviruses: a Decade of
Structural Studies

Fang Li

Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, USA

Receptor recognition by viruses is the first and essential step of viral infections of host cells. It is an important determinant of
viral host range and cross-species infection and a primary target for antiviral intervention. Coronaviruses recognize a variety of
host receptors, infect many hosts, and are health threats to humans and animals. The receptor-binding S1 subunit of coronavi-
rus spike proteins contains two distinctive domains, the N-terminal domain (S1-NTD) and the C-terminal domain (S1-CTD),
both of which can function as receptor-binding domains (RBDs). S1-NTDs and S1-CTDs from three major coronavirus genera
recognize at least four protein receptors and three sugar receptors and demonstrate a complex receptor recognition pattern. For
example, highly similar coronavirus S1-CTDs within the same genus can recognize different receptors, whereas very different
coronavirus S1-CTDs from different genera can recognize the same receptor. Moreover, coronavirus S1-NTDs can recognize
either protein or sugar receptors. Structural studies in the past decade have elucidated many of the puzzles associated with coro-
navirus-receptor interactions. This article reviews the latest knowledge on the receptor recognition mechanisms of coronavi-
ruses and discusses how coronaviruses have evolved their complex receptor recognition pattern. It also summarizes important
principles that govern receptor recognition by viruses in general.

C

oronaviruses (CoV) are a group of common, ancient, and di-
verse viruses. They infect many mammalian and avian species
and cause respiratory, gastrointestinal, and central nervous system
diseases (1, 2). Coronavirus virions contain an envelope, a helical
capsid, and a single-stranded and positive-sense RNA genome. The
lengthoftheirgenomes,whicharethelargestamongallRNAviruses,
typically ranges between 27 and 32 kb. They were named “coronavi-
ruses”becauseoftheprotrudingspikeproteinsontheirenvelopethat
give the virions a crown-like shape (“corona” in Latin means crown).
Coronaviruses belong to the Coronaviridae family in the order of
Nidovirales. They can be classified into at least three major genera,
�, �, and � (formerly group 1, 2, and 3, respectively) (3). Proto-
typic �-genus coronaviruses include human coronavirus NL63
(HCoV-NL63), porcine transmissible gastroenteritis coronavirus
(TGEV), and porcine respiratory coronavirus (PRCV). Prototypic
�-genus coronaviruses include severe acute respiratory syndrome
coronavirus (SARS-CoV), Middle East respiratory syndrome
coronavirus (MERS-CoV), mouse hepatitis coronavirus (MHV),
and bovine coronavirus (BCoV). Prototypic �-genus coronavi-
ruses include avian infectious bronchitis virus (IBV). These three
major coronavirus genera and their prototypic coronaviruses are
the focus of this review article (Fig. 1).
Coronaviruses impose health threats to humans and animals.
Two�-coronaviruses,SARS-CoVandMERS-CoV,arehighlypatho-
genic human pathogens. SARS-CoV caused the SARS epidemic in
2002 to 2003, with over 8,000 infections and a fatality rate of �10%
(4–7). MERS-CoV emerged from the Middle East in 2012. As of 16
October 2014, MERS-CoV had caused 877 infections with a fatality
rate of �36% (http://www.who.int/csr/don/16-october-2014-mers
/en/) (8, 9). HCoV-NL63 from the �-genus is a prevalent human
respiratory pathogen that is often associated with common colds in
healthy adults and acute respiratory diseases in young children (10,
11). Among the animal coronaviruses, TGEV from the �-genus and
MHV from the �-genus cause close to 100% fatality in young pigs
and young mice, respectively (12–15); BCoV from the �-genus and
IBV from the �-genus also cause significant health damage in cattle

and chickens, respectively (16–19). Therefore, research on coronavi-
ruses has strong health and economic implications.
Receptor recognition by viruses is the first and essential step of
viralinfectionsofhostcells(20).Anenvelope-anchoredspikeprotein
mediates coronavirus entry into host cells by first binding to a recep-
tor on the host cell surface and then fusing viral and host membranes
(21, 22). A member of the class I viral membrane fusion proteins
(23–26), the coronavirus spike consists of three segments—an ect-
odomain, a single-pass transmembrane anchor, and a short intracel-
lular tail (27, 28). The ectodomain can be divided into a receptor-
binding S1 subunit and a membrane-fusion S2 subunit. The amino
acid sequences of S1 diverge across different genera but are relatively
conserved within each genus (29). S1 contains two independent do-
mains, an N-terminal domain (S1-NTD) and a C-terminal domain
(S1-CTD, also called S1 C-domain) (Fig. 1) (29). Either or both of
these S1 domains can function as a receptor-binding domain (RBD).
ThebindinginteractionbetweencoronavirusRBDanditsreceptoris
one of the most important determinants of the coronavirus host
range and cross-species infection (2, 30). In addition, coronavirus
RBDs contain major neutralization epitopes, induce most of the host
immune responses, and may serve as subunit vaccines against coro-
navirus infections (31–36). Knowledge about the receptor recogni-
tion mechanisms of coronaviruses is critical for understanding coro-
navirus pathogenesis and epidemics and for human intervention in
coronavirus infections.
Coronaviruses recognize a variety of host receptors (Fig. 1).

Accepted manuscript posted online 26 November 2014

Citation Li F. 2015. Receptor recognition mechanisms of coronaviruses: a decade
of structural studies. J Virol 89:1954–1964. doi:10.1128/JVI.02615-14.

Editor: S. P. Goff

Address correspondence to